DESCRIPTION: (Principal Investigator's) The purpose of this research program is to invent, develop, and apply synthetic methods to the synthesis and study of architecturally complex bioactive natural products. The synthetic strategies to be studied should allow for the rapid and efficient preparation of targeted and allied molecules allowing for the evaluation and study of their biological properties. The program will concentrate in three areas: (a) The synthesis of a structurally unique class of macrocyclic compounds, known as the phomactins. Recently isolated from a marine fungus, these molecules have demonstrated marked biological properties. Specifically, the phomactins can effect the function of platelet-activating factor (PAF). PAF is a compound ubiquitous to the human body and implicated in respiratory, inflammatory, and cardiovascular diseases. While PAF has been the subject of an intense research effort, numerous questions concerning its role in these diseases remain unanswered. Interestingly, while the phomactins inhibit PAF-induced platelet aggregation, no effect on adenosine diphosphate, arachidonic acid, and collagen-induced platelet aggregation has been observed. Thus the phomactins represent a new type of PAF antagonist. (b) The synthesis of a series of novel macrolactones known as the amphidinolides. These compounds have attractive biological features, especially antileukemic properties as well as activity towards rabbit skeletal muscle actomysion ATPase. In addition to their impressive antileukemic activity, these molecules have several striking structural features, including the contrast of lipophilic and hydrophilic moieties as well as the presence of both conjugated and non-conjugated dienes. (c) In conjunction with these synthetic ventures it is planned that new organometallic and free radical reactions be designed and investigated. Particular interests include the development of catalytic methods involving palladium, indium, tin, and silicon as well as a study of the 1,2-Wittig rearrangement in complex molecule synthesis.